Drug Interactions between mitotane and Skyclarys

ADJUST DOSING INTERVAL: Fat-rich food enhances the absorption of mitotane. One study evaluated blood levels of mitotane (o,p'-DDD) after subjects ingested a single dose of 2 g administered using various delivery vehicles (e.g., tablets, granules, milk, chocolate or oil emulsion). Mitotane plasma levels were significantly higher for milk, chocolate, and oil emulsion when compared to those who received tablets or granules alone. In the same study, mitotane levels were evaluated in subjects following long-term treatment (total dose of 200 g over 30 to 60 days) in tablet, oil emulsion, or milk formulations. Significantly higher mean plasma levels were recorded in subjects who received mitotane as an oil emulsion or mixed in milk, when compared to tablets alone. Additionally, the recovery of o,p'-DDD from the feces was about 5 times higher in subjects who received tablets alone, suggesting absorption was reduced when compared to subjects who received mitotane mixed with a fat-rich vehicle (e.g., oil emulsion or milk).

GENERALLY AVOID: Concomitant use of mitotane with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence and sedation.

MANAGEMENT: According to product labeling, mitotane tablets should be taken during meals containing fat-rich food (e.g., milk, chocolate, or oil) and with a full glass of water. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of omaveloxolone, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. When administered with itraconazole, a potent CYP450 3A4 inhibitor, omaveloxolone peak plasma concentration (Cmax) and systemic exposure (AUC) increased 3-fold and 4-fold, respectively. When administered with verapamil, a moderate CYP450 3A4 inhibitor, omaveloxolone Cmax and AUC increased approximately 1.25-fold each. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to omaveloxolone may increase the risk of adverse reactions such as lipid abnormalities and increased aminotransferases and B-type natriuretic peptide (BNP).

ADJUST DOSING INTERVAL: Food may increase the oral bioavailability of omaveloxolone. Coadministration with a high-fat meal (800 to 1000 calories, with approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively) increased omaveloxolone Cmax and AUC by approximately 350% and 15%, respectively, compared to fasted conditions.

MANAGEMENT: Omaveloxolone should be administered on an empty stomach at least 1 hour before eating. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with omaveloxolone.